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Paracrine-stimulated gene expression profile favors estradiol production in breast tumors.
Mol Cell Endocrinol. 2006 Jul 11; 253(1-2):44-55.MC

Abstract

Paracrine interactions between adipose fibroblasts and malignant epithelial cells are essential for structural and hormonal support of breast tumors. Factors derived from malignant epithelial cells inhibit adipogenic differentiation of fibroblasts and upregulate expression of aromatase, which stimulates estrogen synthesis and creates a localized, growth-stimulatory environment. Here, we characterized the gene expression profile of breast adipose fibroblasts in an in vitro model of malignancy to identify other paracrine interactions that support tumor growth. Primary breast adipose fibroblasts from cancer-free women were treated with conditioned media from malignant breast epithelial cells or normal breast epithelial cells, and differences in gene expression were identified by microarray. A total of 79 differentially regulated genes encoding cytokines, enzymes, angiogenic factors, cytoskeletal proteins, extra-cellular matrix remodeling proteins, signal transduction proteins and cell surface receptors were identified, and 6 of these were verified by real-time PCR. Among these, the expression of aldo-keto reductase family 1, member C3 (AKR1C3) was upregulated. AKR1C3 has multiple enzymatic properties, including conversion of estrone to estradiol and androstenedione to testosterone. Immunoreactive AKR1C3 was detected in epithelial and stromal components of benign lesions and ductal carcinomas in situ, and in 59.8% of epithelial and 69.6% of stromal cells in invasive breast carcinomas. AKR1C3 expression was significantly higher in myoepithelial cells surrounding the neoplastic epithelium of ductal carcinoma in situ compared with those surrounding benign epithelial lesions. Importantly, AKR1C3 and aromatase mRNA levels correlated positively in 61 malignant breast tumors (R=0.3967, p=0.00156). Malignant epithelial cell-conditioned medium significantly increased formation of testosterone and estradiol from androstenedione in breast adipose fibroblasts. In conclusion, malignant epithelial cell-derived factors significantly upregulate the enzymes AKR1C3 and aromatase that catalyze a series of complementary reactions to convert the circulating precursor androstenedione to biologically active estradiol in vitro in the stromal fibroblasts, and in vivo, in stromal component of breast tumors.

Authors+Show Affiliations

Department of Obstetrics and Gynecology, Northwestern University, Chicago, IL 60611, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

16735089

Citation

Amin, Sanober A., et al. "Paracrine-stimulated Gene Expression Profile Favors Estradiol Production in Breast Tumors." Molecular and Cellular Endocrinology, vol. 253, no. 1-2, 2006, pp. 44-55.
Amin SA, Huang CC, Reierstad S, et al. Paracrine-stimulated gene expression profile favors estradiol production in breast tumors. Mol Cell Endocrinol. 2006;253(1-2):44-55.
Amin, S. A., Huang, C. C., Reierstad, S., Lin, Z., Arbieva, Z., Wiley, E., Saborian, H., Haynes, B., Cotterill, H., Dowsett, M., & Bulun, S. E. (2006). Paracrine-stimulated gene expression profile favors estradiol production in breast tumors. Molecular and Cellular Endocrinology, 253(1-2), 44-55.
Amin SA, et al. Paracrine-stimulated Gene Expression Profile Favors Estradiol Production in Breast Tumors. Mol Cell Endocrinol. 2006 Jul 11;253(1-2):44-55. PubMed PMID: 16735089.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Paracrine-stimulated gene expression profile favors estradiol production in breast tumors. AU - Amin,Sanober A, AU - Huang,Chiang-Ching, AU - Reierstad,Scott, AU - Lin,Zhihong, AU - Arbieva,Zarema, AU - Wiley,Elizabeth, AU - Saborian,Hossain, AU - Haynes,Ben, AU - Cotterill,Helen, AU - Dowsett,Mitch, AU - Bulun,Serdar E, Y1 - 2006/06/02/ PY - 2006/04/15/received PY - 2006/04/21/accepted PY - 2006/6/1/pubmed PY - 2006/12/16/medline PY - 2006/6/1/entrez SP - 44 EP - 55 JF - Molecular and cellular endocrinology JO - Mol Cell Endocrinol VL - 253 IS - 1-2 N2 - Paracrine interactions between adipose fibroblasts and malignant epithelial cells are essential for structural and hormonal support of breast tumors. Factors derived from malignant epithelial cells inhibit adipogenic differentiation of fibroblasts and upregulate expression of aromatase, which stimulates estrogen synthesis and creates a localized, growth-stimulatory environment. Here, we characterized the gene expression profile of breast adipose fibroblasts in an in vitro model of malignancy to identify other paracrine interactions that support tumor growth. Primary breast adipose fibroblasts from cancer-free women were treated with conditioned media from malignant breast epithelial cells or normal breast epithelial cells, and differences in gene expression were identified by microarray. A total of 79 differentially regulated genes encoding cytokines, enzymes, angiogenic factors, cytoskeletal proteins, extra-cellular matrix remodeling proteins, signal transduction proteins and cell surface receptors were identified, and 6 of these were verified by real-time PCR. Among these, the expression of aldo-keto reductase family 1, member C3 (AKR1C3) was upregulated. AKR1C3 has multiple enzymatic properties, including conversion of estrone to estradiol and androstenedione to testosterone. Immunoreactive AKR1C3 was detected in epithelial and stromal components of benign lesions and ductal carcinomas in situ, and in 59.8% of epithelial and 69.6% of stromal cells in invasive breast carcinomas. AKR1C3 expression was significantly higher in myoepithelial cells surrounding the neoplastic epithelium of ductal carcinoma in situ compared with those surrounding benign epithelial lesions. Importantly, AKR1C3 and aromatase mRNA levels correlated positively in 61 malignant breast tumors (R=0.3967, p=0.00156). Malignant epithelial cell-conditioned medium significantly increased formation of testosterone and estradiol from androstenedione in breast adipose fibroblasts. In conclusion, malignant epithelial cell-derived factors significantly upregulate the enzymes AKR1C3 and aromatase that catalyze a series of complementary reactions to convert the circulating precursor androstenedione to biologically active estradiol in vitro in the stromal fibroblasts, and in vivo, in stromal component of breast tumors. SN - 0303-7207 UR - https://www.unboundmedicine.com/medline/citation/16735089/Paracrine_stimulated_gene_expression_profile_favors_estradiol_production_in_breast_tumors_ DB - PRIME DP - Unbound Medicine ER -